The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these ...two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of NK cells, lymphocytes that play key roles in antiviral and antitumor immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell proinflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFN-γ, which is important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, upregulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFN-γ production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions.
The type 1 interferons, alpha and beta (IFN- alpha / beta ), are comprised of the products of multiple (up to 12) IFN- alpha genes and a single IFN- beta gene. These factors use a common ...heterodimeric receptor, broadly expressed on most cells. The major pathway of intracellular signaling used by IFN- alpha / beta and their receptors accesses the tyrosine kinases, Jak 1 and Tyk 2, activating the signal transducer and activators of transcription (STAT) 1 and STAT2 to form a STAT1/STAT2 heterodimer. Other pathways, however, are also induced. STAT1/STAT2 complexes associate with a p48 protein, identified as the interferon responsive factor (IRF) 9, to form the interferon-stimulated gene factor-3 (ISGF-3). ISGF-3 induces transcription as a result of recognizing interferon stimulated response elements (ISREs) in promoter regions of interferon responsive genes. Although first characterized based on potent antiviral functions, IFN- alpha / beta also mediate a variety of immunoregulatory effects. The immune modulating functions suggest that type 1 IFNs may be important links between innate and adaptive immune responses. IFN- alpha / beta induction of MHC class I expression and activation of natural killer (NK) cell cytotoxicity has long been appreciated. The last few years of research have not only advanced the characterization of these classic IFN activities but have also revealed a number of surprises concerning other biologically important immunoregulatory functions. The strongest evidence is for IFN- alpha / beta enhancement of induction of other IFN- alpha / beta cytokines and IL-15; the apparently contrasting inhibition of IL-12 expression but induction of a high-affinity form of the IL-12 receptor; the shaping of NK cell responses; the complex positive and negative effects on IFN- gamma expression; and effects on dendritic cell (DC) maturation and function. These are reviewed below.
The interface between an infectious agent and its host represents the ultimate battleground for survival: The microbe must secure a niche for replication, whereas the host must limit the pathogen's ...advance. Among the host's arsenal of antimicrobial factors, the type 1 interferons (IFNs) induce potent defense mechanisms against viruses and are key in the host-virus standoff. Viruses have evolved multiple tricks to avoid the immediate antiviral effects of IFNs and, in turn, hosts have adapted use of this innate cytokine system to galvanize multiple additional layers of immune defense. The plasticity that exists in these interactions provides us with a lesson in détente.
NK cell expression and use of the IL-2Rα-chain (CD25), required for the high-affinity IL-2R, remain poorly understood. The studies reported in this article demonstrate that infections with murine CMV ...(MCMV), but not with lymphocytic choriomeningitis virus, induce CD25 on NK cells, along with high levels of IL-12 and IL-18. The cytokines act ex vivo to increase CD25 levels, and IL-12, IL-12R, and STAT4, but not the NK activating receptor Ly49H, are required for peak induction in vivo. All examined NK cell populations are driven into proliferation and incorporate BrdU in response to high ex vivo concentrations of IL-2, but only those from MCMV infection respond to low ex vivo concentrations of IL-2. The numbers of NK cells elicited during MCMV infection are reduced by IL-2 neutralization. Thus, a link between innate and adaptive immunity is established by which composition of innate cytokine responses sets up to promote NK cell use of a factor supporting adaptive responses.
Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction ...in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2.
Natural killer (NK) cells are populations of lymphocytes that can be
activated to mediate significant levels of cytotoxic activity and produce high
levels of certain cytokines and chemokines. NK ...cells respond to and are
important in defense against a number of different infectious agents. The first
indications for this function came from the observations that virus-induced
interferons α/β (IFN-α and -β) are potent inducers of NK
cell-mediated cytotoxicity, and that NK cells are important contributors to
innate defense against viral infections. In addition to IFN-α/β, a
wide range of other innate cytokines can mediate biological functions
regulating the NK cell responses of cytotoxicity, proliferation, and gamma
interferon (IFN-γ) production. Certain, but not all, viral infections
induce interleukin 12 (IL-12) to elicit NK cell IFN-γ production and
antiviral mechanisms. However, high levels of IFN-α/β appear to be
unique and/or uniquely dominant in the context of viral infections and act to
regulate other innate responses, including induction of NK cell proliferation
in vivo and overall negative regulation of IL-12 production. A detailed picture
is developing of particular innate cytokines activating NK cell responses and
their consorted effects in providing unique endogenous milieus promoting
downstream adaptive responses, most beneficial in defense against viral
infections.
NK cells contribute to innate defense during certain viral infections, but the mechanisms for their regulation and delivery of antiviral effects are incompletely understood. A second NK cell ...population, from within T cell populations — NKT cells — has a unique potential to initiate cellular effector mechanisms, including those delivered by NK cells, provided that the antigen for their restricted TCR is induced during infection. If elicited, particular innate cytokine responses promote activation of NK cell cytotoxicity or IFN-γ production. These responses can contribute to defense by mediating antiviral and/or immunoregulatory effects. Roles of positive or negative receptors for target cells in protection against viruses are less clear. Exciting new data indicate that, in at least one system, NK cell receptors that positively signal for activation participate in the recruitment of these cells into antiviral defense mechanisms. Other recent evidence suggests that NKT cells may be important for protection during one viral infection and may be artificially activated by delivery of antigen to promote antiviral defense. Taken together, these recent advances in the characterization of the NK and NKT cell responses are filling in the details of the complex and critical events taking place, at the earliest times after challenge, to promote resistance to viruses.
CpG-DNA or its synthetic analog CpG-ODN activates innate immunity through Toll-like receptor 9 (TLR9). However, the mechanism of TLR9 activation by CpG-DNA remains elusive. Here we have identified ...HMGB1 as a CpG-ODN–binding protein. HMGB1 interacts and preassociates with TLR9 in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and hastens TLR9’s redistribution to early endosomes in response to CpG-ODN. CpG-ODN stimulates macrophages and dendritic cells to secrete HMGB1; in turn, extracellular HMGB1 accelerates the delivery of CpG-ODNs to its receptor, leading to a TLR9-dependent augmentation of IL-6, IL-12, and TNFα secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNFα, and iNOS response to CpG-ODN. However, lack of intracellular TLR9-associated HMGB1 can be compensated by extracellular HMGB1. Thus, the DNA-binding protein HMGB1 shuttles in and out of immune cells and regulates inflammatory responses to CpG-DNA.
Host responses to infectious challenges include initial events elicited directly by agent structures distinct from host determinants, activation of innate immune system components by the products of ...initial events, and the shaping of downstream adaptive immunity by these initial/innate responses. The picture emerging from viral infections is that viral structures interact with intracellular signaling pathways to induce expression of the type 1 interferons, IFN-α/β. In addition to mediating direct antiviral effects, these cytokines play dominant roles in regulating innate and adaptive immune responses to infection. In particular, IFN-α/β acts to inhibit interleukin-12 (IL-12) expression and IL-12 activation of innate natural killer (NK) cell IFN-γ production, while inducing NK cell cytotoxicity and proliferation, and promoting adaptive T cell IFN-γ responses. Although certain viral infections do elicit initial/innate IL-12 and NK-cell-produced IFN-γ, endogenous IFN-α/β also controls the magnitudes of these responses. Thus, the pathways activated, to dominantly regulate innate and adaptive immune responses during viral infections, are being defined.
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